Colon cancer cell switch helps evades treatment

Researchers in Germany have discovered that colon cancers are often resistant to existing drug treatments because they are composed of two different cell types that can replace each other when one cell type is killed. The study, 'Targeting tumor cell plasticity by combined inhibition of NOTCH and MAPK signaling in colon cancer', published in the Journal of Experimental Medicine, suggests that combination therapies targeting both cell types at once may be more effective at treating colorectal cancer, the third highest cause of cancer-related death in the United States.

Early-stage colon cancers can be surgically removed but later stages of the disease require more targeted treatments, including therapies designed to block the MAPK signalling pathway that promotes colon cancer progression.

"However, targeting MAPK signalling has limited effects and usually prolongs patient survival by only a few months. We therefore urgently need radical improvements in targeted therapy for patients with colorectal cancer," said Professor David Horst of the Charité University Hospital in Berlin, Germany.

One potential alternative is to target the NOTCH signalling pathway, which is also thought to drive colon cancer progression even though, in bladder cancer, it suppresses MAPK signalling. However, initial trials of NOTCH pathway inhibitors have so far yielded disappointing results.

Horst and colleagues examined over 300 patient samples and found that the NOTCH pathway was not activated in all colon cancer cells. Cells in the middle of tumours showed signs of active NOTCH signalling but reduced MAPK activity. This population of cells appeared to be highly proliferative.

Cells at the edges of colon cancers, in contrast, showed high levels of MAPK signalling but little NOTCH pathway activity. This population of cells was less proliferative but appeared to be undergoing the initial stages of metastasis, in which colon cancer cells invade and spread to other tissues.

Human colon cancers contain two populations of cancer cells, one at the tumor edge in which the MAPK pathway is highly active (indicated by green staining and the white arrowhead), and one in the center of tumor in which the NOTCH pathway is activated (indicated by red staining and the white arrow). Credit: Schmidt et al., 2018

These two different cell types could also be seen in the tumours formed by human colon cancer cells injected into mice. The tumours quickly lost their MAPK-active cells when the researchers treated these mice with the MAPK pathway inhibitor selumetinib, but the number of NOTCH-active cells increased so that there was minimal disruption to the tumours’ overall growth. And, after stopping selumetinib treatment, some of these NOTCH-active cells gave rise to new MAPK-active cells at the tumour edge.

Human colon cancer cells injected into mice form tumors (left) consisting of both MAPK-active cells (green) and NOTCH-active cells (red). Treatment with the MAPK inhibitor selumetinib results in tumors consisting of NOTCH-active cells only (center), but after treatment is stopped, the NOTCH-active cells give rise to new MAPK-active cells, restoring the tumors' original composition (right). Credit: Schmidt et al., 2018

In contrast, treatment with the NOTCH pathway inhibitor dibenzazepine eliminated NOTCH-active cells from tumours but the population of MAPK-active cells expanded and gave rise to new NOTCH-active cells once dibenzazepine treatment was discontinued.

"This suggests that colon cancers may evade targeted treatment against MAPK or NOTCH signalling by a reversible shift in the predominating pathway activity," said Horst. "However, when combining both therapies to target both cell populations, we found strong repressive effects on tumour cell proliferation and increased cell death, resulting in slower tumour growth and prolonged survival times compared to either treatment alone."

Horst and colleagues note that targeting the NOTCH pathway alone may even be detrimental to colon cancer patients, if it results in an increased number of MAPK-active cells poised to undergo metastasis.

"Our data support a new concept for cancer therapy that advocates specific and simultaneous targeting of several different tumour cell subpopulations to strongly improve therapy response," concluded Horst. "Further preclinical and clinical trials may therefore reveal if combined MAPK and NOTCH inhibition, in addition to established chemotherapeutic protocols, can improve therapy response in patients with colorectal cancer."